HERIZON-BTC-302: A phase III study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line (1L) treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC)

BackgroundZanidatamab (zani) is a humanised, IgG1-like, HER2-targeted bispecific antibody that simultaneously binds to 2 non-overlapping domains on HER2. Zani is being investigated for the treatment of HER2-expressing solid tumours, including BTC. In the phase 2 HERIZON-BTC-01 trial, zani monotherapy demonstrated promising antitumour activity in 80 patients (pts) with previously treated HER2-positive BTC. Confirmed objective response rate (cORR) was 41.3% with rapid and durable responses and a manageable safety profile. This phase 3 trial is assessing zani + SOC therapy vs SOC alone for 1L treatment of HER2-positive advanced/metastatic BTC.Trial designThis ongoing, global, phase 3, randomised, open-label trial (NCT06282575) is investigating the efficacy and safety of zani with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as 1L treatment for pts with advanced HER2-positive BTC. Eligibility criteria include: ≥18 years of age; locally advanced, unresectable or metastatic HER2-positive BTC by immunohistochemistry and in situ hybridization assay (IHC 3+ or IHC 2+/ISH+); and Eastern Cooperative Oncology Group performance status ≤1. Pts may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for pts who completed it for breast cancer >5 years prior to BTC diagnosis. Eligible pts will be randomised to receive zani (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight <70 kg] or 2400 mg IV [ body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD-1/L1 inhibitor or CisGem alone ± a PD-1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in pts with IHC 3+ tumors. Secondary/exploratory endpoints include: overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events and patient-reported outcomes. The study is currently recruiting pts.Clinical trial identificationNCT06282575, February 28, 2024.Editorial acknowledgementThis study was supported by Jazz Pharmaceuticals. Medical writing support, under the direction of the authors, was provided by Mai Moawed, BPharm, of CMC Affinity, a division of IPG Health Medical Communications.Legal entity responsible for the studyJazz Pharmaceuticals.FundingJazz Pharmaceuticals.DisclosureT. Macarulla Mercade: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd., Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp & Dohme, Novocure, QED Therapeutics Inc., Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZeneca, Bayer, BeiGene, BioLineRx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-La Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, MedImmune, Merrimack, Millenium, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica� – SEOM, Sociedad Europea de Oncología Médica - ESMO; Other, Editorial Board: GI Annals of Oncology. J.J. Harding: Financial Interests, Personal, Research Funding: NCI P30-CA008748, NCI U01 CA238444 04, the Society of Memorial Sloan Kettering Cancer Center, Experimental Therapeutics Center, Cycle for Survival, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Debiopharm, Lilly, Genoscience, Incyte, Kinnate Biopharma, Loxo Lilly, Novartis, Polaris, Pfizer, Tvardi, Zymeworks, Yiviva; Financial Interests, Personal, Other, Consulting fee: Adaptimmune; Financial Interests, Personal, Advisory Board, Consulting fee: AstraZeneca, Bristol Myers Squibb, Exelixis, Elevar, Eisai, Hepion, Imvax, Merck data and safety monitoring board (DSMB), Medivir, QED, RayzeBio, Servier, Tempus, Tyra; Non-Financial Interests, Personal, Advisory Board, Consulting fee: Genoscience, Zymeworks. S. Pant: Financial Interests, Personal, Other, Zymeworks: Zymeworks; Financial Interests, Personal, Other, Ipsen: Ipsen; Financial Interests, Personal, Other, Novartis: Novartis; Financial Interests, Personal, Other, Janssen: Janssen; Financial Interests, Personal, Other, Boehringer Ingelheim: Boehringer Ingelheim; Financial Interests, Personal, Other, AskGene Pharma: AskGene Pharma; Financial Interests, Institutional, Funding, Company: Mirati Therapeutics Recipient: Your Institution: Mirati Therapeutics; Financial Interests, Institutional, Coordinating PI, Company: Lilly Recipient: Your Institution: Lilly; Financial Interests, Institutional, Coordinating PI, Company: Xencor Recipient: Your Institution: Xencor; Financial Interests, Institutional, Coordinating PI, Company: Novartis Recipient: Your Institution: Novartis; Financial Interests, Institutional, Coordinating PI, Company: Rgenix Recipient: Your Institution: Rgenix; Financial Interests, Institutional, Coordinating PI, Company: Bristol Myers Squibb Recipient: Your Institution: Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI, Company: Astellas Pharma Recipient: Your Institution: Astellas Pharma; Financial Interests, Institutional, Coordinating PI, Company: Frame wave Recipient: Your Institution: Company: Framewave Recipient: Your Institution; Financial Interests, Institutional, Coordinating PI, Company: 4D Pharma Recipient: Your Institution: 4D Pharma; Financial Interests, Institutional, Coordinating PI, Company: Boehringer Ingelheim Recipient: Your Institution: Boehringer Ingelheim; Financial Interests, Institutional, Coordinating PI, Company: NGM Biopharmaceuticals Recipient: Your Institution: NGM Biopharmaceuticals; Financial Interests, Institutional, Coordinating PI, Company: Janssen Recipient: Your Institution: Janssen; Financial Interests, Institutional, Coordinating PI, Company: Arcus Biosciences Recipient: Your Institution: Arcus Biosciences; Financial Interests, Institutional, Coordinating PI, Company: Elicio Therapeutics Recipient: Your Institution: Elicio Therapeutics; Financial Interests, Institutional, Coordinating PI, Company: Bionte Recipient: Your Institution: Bionte; Financial Interests, Institutional, Coordinating PI, Company: Ipsen Recipient: Your Institution: Ipsen; Financial Interests, Institutional, Coordinating PI, Company: Zymeworks Recipient: Your Institution: Zymeworks; Financial Interests, Institutional, Coordinating PI, Company: Pfizer Recipient: Your Institution: Pfizer; Financial Interests, Institutional, Coordinating PI, Company: ImmunoMET Recipient: Your Institution: ImmunoMET; Financial Interests, Institutional, Coordinating PI, Company: Immuneering Recipient: Your Institution: Immuneering; Financial Interests, Institutional, Coordinating PI, Company: Amal Therapeutics Recipient: Your Institution: Amal Therapeutics. X. Wu: Financial Interests, Personal, Full or part-time Employment: Jazz Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Jazz Pharmaceuticals. P. Garfin: Financial Interests, Personal, Full or part-time Employment: Jazz Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Jazz Pharmaceuticals; Financial Interests, Personal, Other, former employee and owned stock or stock options: Zymeworks. T. Okusaka: Financial Interests, Personal, Advisory Board: Eisai, Nihon Servier, AstraZeneca, Fujifilm Toyama Chemical; Financial Interests, Personal, Invited Speaker: AstraZeneca, Eisai, Chugai Pharma, Nihon Servier, Incyte, Novartis, Daiichi Sankyo, Taiho, Yakult, Myriad Genetics, Kyowa Kirin, Ono; Financial Interests, Institutional, Local PI: AstraZeneca, Eisai, Bristol Myers Squibb, Incyte, Syneos Health, Chiome Bioscience, Sysmex.